Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated genes kmt5b and hdlbpa , defined by increased activity mainly in the thalamus and mesencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences, localized to the diencephalon in three cases and more widespread in others. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes for three mutants, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multimodal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.

中文翻译：

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具有自闭症风险突变的斑马鱼的间脑发育和神经肽能通路中断

数以百计的人类突变与自闭症和相关疾病有关，但其中许多突变基因在脊椎动物神经发育过程中的功能尚不清楚。我们生成了 27 个斑马鱼突变体，这些突变体具有推定的蛋白质截断突变或对应于 17 个人类基因中自闭症风险等位基因的特定错义变异。我们观察到幼虫阶段的基线和刺激驱动的行为变化，以及作为幼虫测试的品系中的社会行为差异。全脑成像活动揭示了不相关基因 kmt5b 和 hdlbpa 突变的活动图，其定义是主要在丘脑和中脑活动增加。17 个风险基因中的 7 个突变导致大脑大小的巨大差异，在 3 个病例中定位于间脑，在其他情况下更为普遍。使用 RNA 测序，我们进一步定义了三种突变体观察到的表型的分子驱动因素，确定了神经肽信号传导、神经元成熟和细胞增殖中的靶向破坏。这种多模式筛选提名了可能导致自闭症易感性的大脑区域、细胞类型和分子途径。